It is estimated that 5.3 million Americans have Alzheimer's disease (AD), and that the number and proportion of Americans affected by AD is expected to grow rapidly in the next several decades. The striking increase in numbers of individuals with AD has been recognized as an "epidemic" with substantial personal and societal consequences which begin early on in the course of illness. Nearly 10 million Americans provide unpaid care for a person with AD or other dementia, and the high levels of stress and negative health outcomes associated with family care giving are well documented. Cost of health and long-term care services to this population are estimated to be over three times as high as those of elderly people without AD. It is therefore not surprising that Comparative Effectiveness Research (CER) on pharmacological and non- pharmacological treatments for individuals with Alzheimer's disease (AD) and other dementias ranks in the first quartile of the 100 Initial Priority Topics for CER recently recommended by the Institute of Medicine. Our proposal, focusing on patient reported outcomes in individuals with Mild Cognitive Impairment, mild/moderate AD and those at-risk for AD, is based on the premise that valid measurement of patient-oriented outcomes is essential to the conduct of CER. This proposal builds on the Patient Reported Outcomes Measure Information System (PROMIS), an NIH Roadmap project designed to improve our ability to measure patient-reported symptoms in a wide spectrum of chronic diseases and conditions. PROMIS has made significant strides in development and testing of item batteries across a wide range of domains. An important remaining goal is to assess the performance and research utility of the PROMIS measures against commonly used (Legacy) measures. We propose to conduct validation studies of two existing PROMIS domains (physical function and depression) in a well-characterized sample of 300 patients, and to extend the validation efforts of PROMIS by proposing the first evaluation of proxy response (n=250) to PROMIS measures in an adult population. We have chosen these two domains because of all PROMIS domains, they are central to the CER in AD and other dementias. We propose a two-phase project. In Phase 1, an expert panel will select items from the extensive physical function PROMIS battery that are most appropriate for use in our target population. In Phase 2, we will validate existing physical function and depression PROMIS batteries (PFDPB) within and across the three sub- groups in our sample;evaluate the relative ability of PFDPB and Legacy measures to detect meaningful clinical change in each sub-group by comparing PFDPB and Legacy measures in subjects at two time points;evaluate the potential use of PFDPB as proxy report measures within and across three sub-groups at two time points;and compare simulated computer-based adaptive testing of PROMIS measures to fixed administration. Project results will provide valuable and timely information to researchers assessing the relative value of pharmacological and non-pharmacological interventions for maintaining or improving patient physical and mental function. PUBLIC HEALTH RELEVANCE: This work will contribute to the success of Comparative Effectiveness Research involving individuals at risk for Alzheimer's disease (AD) as well as those already affected by it. By rigorously evaluating alternative measures of patient-reported outcomes in this population, it will provide valuable and timely information to researchers assessing the relative value of pharmacological and non-pharmacological interventions in maintaining or improving patient physical and mental function.